A number of different lines of evidence suggest a strong role for heredity in the etiology of schizophrenia, a relatively common, chronic and debilitating psychiatric disorder. Linkage and association studies, however, have not to date been successful in elucidating the underlying genetic mechanisms. We request in this application five years of continued support to detect, localize and characterize susceptibility genes contributing to schizophrenia. This work will be performed using data from the recently completed Irish Study of High Density Schizophrenia Families (ISHDSF). The ISHDSF was derived from a systematic ascertainment of multiplex schizophrenia pedigrees in 37 facilities covering over 90% of the relatively homogeneous population of Ireland and Northern Ireland. The linkage sample contains 264 pedigrees and DNA from 1,404 individuals. The primary specific aim of this project is to complete a systematic genome scan of the ISHDSF by using highly polymorphic DNA markers located approximately every 10 centimorgans. Follow-up genotyping will be performed in genomic regions showing preliminary evidence of linkage. Statistical analyses will be performed using standard parametric and nonparametric methods, as well as by techniques recently developed by our group that may increase power to detect linkage for complex traits such as schizophrenia. A second aim is to test genes in these regions of possible linkage, i.e., "positional" candidate genes, to identify which gene(s) in the region is producing the linkage signal. Integrating I) a large, systematically gathered and carefully characterized clinical sample, ii) both standard and novel statistical methods and iii) the latest genomic and molecular genetic techniques, which includes automation and utilization of the methods and reagents supplied by the Human Genome Project, this proposal provides a realistic opportunity to overcome the difficulties with prior studies and successfully identify and characterize genes that significantly influence the susceptibility to schizophrenia.